Thiazolylhydrazone dervatives as inhibitors for insect N-acetyl-β-D-hexosaminidase and chitinase

Article abstract of DOI:10.1016/j.cclet.2019.11.035

Insect chitinase and N-acetyl-β-D-hexosaminidases (Hex) are potential targets for developing new pesticides. Here, a series of thiazolylhydrazones I (with substituted group R₁ at N3) and II (with substituted group R₁ at N2) were designed, synthesised and evaluated as competitive inhibitors of OfHex1 and OfChi-h, from the agricultural pest Ostrinia furnacalis. Derivatives I-3d and II-3d, with phenoxyethyl group at R₁, demonstrated the best inhibitory activities against OfHex1 and OfChi-h. Molecular docking analysis indicated that the branched conformation compound II-3d (K_i = 1.5 μmol/L) formed more hydrogen bonds with OfHex1 than the stretched conformation compound I-3d (K_i = 5.9 μmol/L). The differences in compounds’ binding conformations with OfChi-h explained differences in inhibitory activity of compounds I-3d (K_i = 1.9 μmol/L) and II-3d (K_i = 4.1 μmol/L). This work suggests a novel scaffold for developing specific Hex and Chi-h inhibitors.

Full text of DOI:10.1016/j.cclet.2019.11.035

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Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Thiazolylhydrazone dervatives as inhibitors for insect
N-acetyl-β- -hexosaminidase and chitinase
D
Huibin Yanga,b,1, Huitang Qic,1, Zesheng Haob, Xusheng Shaoa, Tian Liuc, Qing Yangc,
,
*
Xuhong Qiana,
*
a
Shanghai Key Laboratory of Chemical Biology, Institute of Pesticides and Pharmaceuticals, School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
b
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals Research and Development Co., Ltd., Shenyang
110021, China
c
School of Bioengineering, Dalian University of Technology, Dalian 116024, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Insect chitinase and N-acetyl-β-D-hexosaminidases (Hex) are potential targets for developing new
Received 8 October 2019
Received in revised form 18 November 2019
Accepted 20 November 2019
Available online xxx
pesticides. Here, a series of thiazolylhydrazones I (with substituted group R1 at N3) and II (with
substituted group R1 at N2) were designed, synthesised and evaluated as competitive inhibitors of
OfHex1and OfChi-h, from the agricultural pest Ostrinia furnacalis. Derivatives I-3d and II-3d, with
phenoxyethyl group at R1, demonstrated the best inhibitory activities against OfHex1 and OfChi-h.
Molecular docking analysis indicated that the branched conformation compound II-3d (Ki = 1.5
formed more hydrogen bonds with OfHex1 than the stretched conformation compound I-3d
(Ki = 5.9 mol/L). The differences in compounds’ binding conformations with OfChi-h explained
differences in inhibitory activity of compounds I-3d (Ki = 1.9 mol/L) and II-3d (Ki = 4.1 mol/L). This
work suggests a novel scaffold for developing specific Hex and Chi-h inhibitors.
mmol/L)
Keywords:
N-acetyl-β-
Chitinase
Inhibitor
Chitin
D-hexosaminidase
m
m
m
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Structure-activity relationship
Thiazolylhydrazone derivatives
Molecular docking
Heterocyclic compounds are an important role building block in
medicinal chemistry. Thiazolidinones have been extensively
investigated over recent decades for a varied range of biological
activities, including antifungal [1], antiparasitic [2], antimicrobial
[3], antioxidant [4], anticonvulsant [5], anti-HIV [6], anti-inflamma-
tory [7], anti-tuberculosis [8], and anti-tumour activities [9].
Thiazolylhydrazone derivatives, with a R1R2C = N-N = substituent
in the 2-position of thiazolidin-4-one, have been studied for their
biological properties, such as antiparasitic [2,10], antifungal [11],
antiurease [12] and antiviral activities [13].
(Hex; EC 3.2.1.52) [18], cooperate with each other to facilitate the
degradation of chitin. The chitinase can act on random positions of
the chitin polymer chain to produce chitooligosaccharides [19,20],
while Hex is responsible for hydrolyzing chitooligosaccharides to
N-acetyl-D-glucosamine during chitin degradation [18,21]. Be-
cause of the absence of chitin from vertebrates and higher plants,
small molecules inhibitors against chitinase and Hex are promising
potential targets for pesticide development.
Reported GH20 inhibitors have varied chemical structures.
Some are carbohydrate-based inhibitors, such as DNJNAc and its
derivatives [22–25], GDL and its derivative PUGNAC [26–29], NTA-
glucal [30], 6-Ac-CAS [31,28], NAG-thiazoline and its derivative
NMAGT [32,33], LNB-thiazoline [34] and TMG-chitotriomycin [35].
Non-carbohydrate-based GH20 inhibitors include naphthalimides
[36], pyrimethamine and its derivatives [37]. Small molecules
against GH18 chitinases have been reported. The pseudotrisac-
charide allosamidin isolated from the Streptomyces sp. [38],
cyclopentapeptides argifin isolated from Gliocladium sp. FTD-
0668 [39], argadin isolated from Clonostachys sp. FO-7314 [40],
Chitin, a linear homopolymer of N-acetyl-β-D-glucosamines and
a major structural component of insect cuticles, plays an important
role in the molting [14–16]. In the degradation system of insect
chitin, two glycoside hydrolase family members, the glycosyl
hydrolase family 18 (GH18) chitinase (EC 3.2.1.14) [17] and the
glycosyl hydrolase family 20 (GH20) β-N-acetylhexosaminidase
* Corresponding authors.
E-mail addresses: qingyang@dlut.edu.cn (Q. Yang), xhqian@ecust.edu.cn
cyclo(L-Arg-D-Pro) from Pseudomonas sp. IZ208 [41], chitobiose and
chitotriose thiazolines [42], xanthine derivatives [43], and CI-4
[44,45], all exhibit effective inhibitory activities. However, it is
(X. Qian).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.cclet.2019.11.035
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: H. Yang, et al., Thiazolylhydrazone dervatives as inhibitors for insect N-acetyl-β-D-hexosaminidase and
chitinase, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.11.035

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Scheme 1. Overview of synthetic methods for 3aÀd. Reagents and conditions: (i) thiosemicarbazide, EtOH, acetic acid (cat.), r.t., 15 h; (ii) MeOH, CH3COONa, reflux, 5 h; (iii)
CH3CN, K2CO3, reflux, 5 h.
Scheme 2. Overview of synthetic methods for 6aÀd. Reagents and conditions: (i) R2CHO, EtOH, acetic acid (cat.), r.t.,15 h; (ii) BrCH2COOEt, MeOH, CH3COONa, reflux, 5 h; (iii)
chloromethylbenzene, CH3CN, K2CO3, reflux, 5 h.
Scheme 3. Overview of synthetic methods for I-3b. Reagents and conditions: (i) H2NNH2
BrCH2COOEt, MeOH, CH3COONa, reflux, 5 h.
Á
H2O, EtOH, reflux, 6 h; (ii) isothiocyanatomethylbenzene, EtOH, reflux, 3 h; (iii)
Fig. 1. The crystal structures and chemical shifts of 1H NMR of compounds I-3a (A) and II-3a (B).
more challenging to drive these leads into large-scale application
because of poor physicochemical properties or complex synthetic
chemistry.
OfHex1 [46] and OfChi-h [47], from the agricultural pest Ostrinia
furnacalis, have been demonstrated to function exclusively in chitin
degradation. Previously, our group reported N3 substituted
thiazolylhydrazone compounds as OfHex1 inhibitors [48], and
we were surprised to observe the by-product N2 substituted
thiazolylhydrazone compounds during the synthesis of N3
substituted thiazolylhydrazone. Only relatively few researches
Please cite this article in press as: H. Yang, et al., Thiazolylhydrazone dervatives as inhibitors for insect N-acetyl-β-D-hexosaminidase and
chitinase, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.11.035

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3
Table 1
Inhibitory activities of compounds I and II against OfHex1 and OfChi-h.
R1
R2
Compd.
Inhibitory rate (%, 10
m
mol/L)
OfChi-h
Inhibitory rate (%, 1
m
mol/L)
OfChi-h
OfHex1
OfHex1
I-3b
II-3b
62.6 Æ 0.3
72.8 Æ 1.7
62.0 Æ 3.2
60.1 Æ 3.0
25.7 Æ 3.1
31.5 Æ 7.1
26.0 Æ 1.8
27.9 Æ 2.3
I-3c
II-3c
20.6 Æ 6.3
67.7 Æ 0.4
18.0 Æ 1.0
23.1 Æ 0.7
6.8 Æ 2.9
1.9 Æ 1.5
5.3 Æ 0.2
30.3 Æ 0.2
I-3d
II-3d
65.8 Æ 3.4
81.3 Æ 0.5
79.6 Æ 0.1
59.2 Æ 0.5
29.0 Æ 4.5
42.9 Æ 1.6
38.7 Æ 1.2
28.6 Æ 2.4
I-6a
II-6a
38.3 Æ 0.2
67.9 Æ 0.2
62.3 Æ 1.8
33.8 Æ 3.8
10.3 Æ 3.3
29.9 Æ 2.5
30.1 Æ 1.9
12.6 Æ 2.0
I-6b
II-6b
50.2 Æ 3.4
55.8 Æ 0.1
53.7 Æ 0.7
11.1 Æ 1.9
18.1 Æ 0.9
25.9 Æ 0.6
23.1 Æ 1.3
2.3 Æ 2.1
I-6c
II-6c
37.4 Æ 0.9
47.7 Æ 6.4
23.7 Æ 1.4
37.8 Æ 5.0
11.2 Æ 1.8
20.8 Æ 0.3
7.0 Æ 0.6
9.9 Æ 1.3
I-6d
II-6d
45.5 Æ 0.6
44.4 Æ 0. 1
32.9 Æ 0.0
11.4 Æ 0.3
16.3 Æ 0.8
15.5 Æ 3.0
11.0 Æ 2.1
1.3 Æ 0.8
on the exocyclic N substituted thiazolylhydrazone compounds
have been reported. In a continued effort in search for biologically
active molecules, here we report the synthesis of thiazolylhy-
drazone derivatives and their inhibitory activities against OfHex1
and OfChi-h. We also investigated the inhibitory mechanisms of
these compounds using structure-based molecular docking.
General experimental, synthesis, characterizations of new
compounds can be found in Supporting information. The N2
substituted thiazolylhydrazone II were isolated as by-product
substituted group R1 was at the exocyclic N2 position, and the
configuration of the N(1)=C(11) double bonds was E. When
comparing the 1H NMR data of compounds II with I, the chemical
shift of CH2 protons of substituted R1 of II (such as II-3a, 5.35 ppm)
appeared at a higher frequency due to the conjugative effect of the
N(1)=C(11) double bonds with naphthalene ring than one of
compound I (such as I-3a, 4.53 ppm).
The inhibitory activities of thiazolylhydrazone derivatives I and
II against OfHex1 and OfChi-h are outlined in Table 1. Some of the
during the synthesis of thiazolyhydrazone
I
according to
compounds exhibited good inhibitory activities at 1
10 mol/L. Our previous work investigating the structure-activity
relationships of the thiazolylhydrazone derivatives against
mmol/L and
previously reported method [48] (Schemes 1 and 2). Compounds
I-3a, I-3c and I-3d had been reported in our previous work [48].
The Rf values of thiazolyllhydrazone I and II is about 0.8 and 0.2 in
solvent of ethyl acetate-petroleum ether (1:1), respectively, and
the ratio of thiazolylhydrazone I to II afforded was approximately
9:1. To confirm the regiochemistry, the N3 substituted thiazo-
lylhydrazones were synthesised by the route illustrated in
Scheme 3. The geometric configuration of double bond and the
regiochemistry were further established by X-ray analysis of
compounds I-3a (CCDC No. 1851329) and II-3a (CCDC No.
1912786). As shown in Fig. 1, for thiazolylhydrazone I, the
substituted group R1 was at N3 position of thiazoline ring, and
the configurations of the double bonds N(2)=C(12) and N(1)=C(11)
m
I
OfHex1 reported the stretched conformation. Interestingly, the
branched conformation of thiazolylhydrazone derivatives II, with
aromatic groups at the N2 atom, such as benzyl (3b) and
phenoxyethyl (3d), exhibited potent inhibitory activity. Further
studies then focused on the naphthalene ring R2. The inhibitory
activities of the resultant derivatives were weakly influenced by
either the substitutes or their position on the naphthalene ring
(compare 3b with 6a and 6b). However, replacement of the
naphthalene ring with benzene, as in compounds 6c and 6d,
resulted in a significant inhibitory activity decrease. Gratifyingly, it
was found that the thiazolylhydrazone derivatives I and II
exhibited promising inhibitory activity against OfChi-h. In
were
Z and E, respectively. For thiazolylhydrazone II, the
Please cite this article in press as: H. Yang, et al., Thiazolylhydrazone dervatives as inhibitors for insect N-acetyl-β-D-hexosaminidase and
chitinase, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.11.035

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particular, compounds I-3d and II-3d were found to display
considerable activity against OfHex1 and OfChi-h (Fig. 2).
predicted different binding modes of I-3d (Ki = 5.9
and II-3d (Ki = 1.5 mol/L, Fig. 2B) could explain the difference in
inhibitory activity.
Interestingly, experiments showed that compound I-3d (Ki =
mol/L, Fig. 2C) has better inhibitory activity against OfChi-h
than compound II-3d (Ki = 4.1 mol/L, Fig. 2D). As shown in Fig. 3D,
mmol/L, Fig. 2A)
m
To further explore possible binding modes of these compounds,
molecular docking studies were carried out using the OfHex1 (PDB
code: 3NSN) and OfChi-h (PDB code: 5GQB) as templates. The
predicted docking results reveal that the thiazolylhydrazone
derivatives bind in the active sites of OfHex1 and OfChi-h with
different modes (Fig. 3). As shown in Fig. 3A, compound I-3d binds
1.9
m
m
the compound I-3d binds the entire active pocket of OfChi-h in a
stretched conformation. The naphthalene ring is sandwiched by
Trp268 and Trp389, and the phenoxyethyl group occupies the
hydrophobic patch comprised by Phe184, Thr269 and Leu270. The
oxygen atom of the phenoxyethyl group forms a hydrogen bond
with the Trp268 residue. The N1 and N2 atoms form hydrogen
bonds with Glu308, stabilizing the binding conformations. While
the mechanism of interaction of II-3d with OfChi-h is different
from that of I-3d, the naphthalene ring occupied the hydrophobic
patch comprised by Phe184, Thr269 and Leu270, the oxygen atom
of the thiazolinone ring only forms a hydrogen bond with the
Leu352 residue (Fig. 3E). The superimposition of compound I-3d
and II-3d reveals that the differences in the compounds’ binding
conformations with OfChi-h explained the differences in their
inhibitory activity (Fig. 3F).
the entire active pocket of OfHex1 via hydrogen bonds,
p-p
stacking and van der Waals interactions. The naphthalene and
thiazolinone rings binds the À1 and +1 subsites and stack with
Trp524 and Trp490, respectively. The oxygen atom of the
thiazolinone ring forms a hydrogen bond with the Glu328 and
Glu526 residue. The phenoxyethyl group binds a subpocket formed
by Trp483 and Asn489 on Loop478-496, and Gln527 via van der
Waals interactions (Fig. 3A). In the docked structure of OfHex1 in
complex with II-3d, the N1 and N2 atoms of the linker form
hydrogen bonds with the Glu328, Glu526 and Trp490 residues,
respectively. The N3 atom forms a hydrogen bond with Glu526, and
the oxygen atom of thiazolinone ring forms a hydrogen bond with
the Gln527 and Asn489 residues (Fig. 3B). Compound II-3d forms
more hydrogen bonds with OfHex1 than compound I-3d. The
superimposition of compound I-3d and II-3d reveals that two
compounds bind in the À1 and +1 subsites of OfHex1 (Fig. 3C). The
In summary, we have designed, prepared and evaluated a series
of thiazolylhydrazone derivatives I and II as potential inhibitors of
OfHex1 or OfChi-h. To further explore possible binding modes of
Fig. 2. Inhibitory kinetics of compounds I-3d (A), II-3d (B) against OfHex1 and I-3d (C), II-3d (D) against OfChi-h.
Fig. 3. Proposed binding modes of compounds I-3d and II-3d to the enzymes OfHex1 and OfChi-h respectively: (A) Binding mode I-3d in the active pocket of OfHex1. The
compound I-3d was shown in green. The hydrogen bonds were shown in black dashes. (B) Binding mode of II-3d in the active pocket of OfHex1. The compound II-3d was
shown in magenta. (C) Superimposition of compound I-3d and II-3d in the active pocket of OfHex1. (D) Binding mode I-3d in the active pocket of OfChi-h. (E) Binding mode of
II-3d in the active pocket of OfChi-h. (F) Superimposition of compounds I-3d and II-3d in the active pocket of OfChi-h.
Please cite this article in press as: H. Yang, et al., Thiazolylhydrazone dervatives as inhibitors for insect N-acetyl-β-D-hexosaminidase and
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Please cite this article in press as: H. Yang, et al., Thiazolylhydrazone dervatives as inhibitors for insect N-acetyl-β-D-hexosaminidase and
chitinase, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.11.035